CN1174031A - Diclofenac sodium skin-penetrating delayed plaster - Google Patents
Diclofenac sodium skin-penetrating delayed plaster Download PDFInfo
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- CN1174031A CN1174031A CN 97109086 CN97109086A CN1174031A CN 1174031 A CN1174031 A CN 1174031A CN 97109086 CN97109086 CN 97109086 CN 97109086 A CN97109086 A CN 97109086A CN 1174031 A CN1174031 A CN 1174031A
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- diclofenac sodium
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Abstract
The delayed transdermal plaster is produced by mixing the main medicine dichlofenac sodium, hydrophilic pressure sensitive detaching agent and composite transdermal promoter, painting the material on paper substrate, and transfer composition with PVC or non-woven back material. The said plaster is painted in affected part for transdermal absorption, and local medicine density in painted part is greatly higher than medicine density in blood. It has obvious antiphlogosis and analgesia effect, long effective period and no irritation and poor effect.
Description
The invention discloses the diclofenac sodium skin-penetrating delayed plaster of a kind of novel medicament percutaneous controlled-release treatment usefulness, it belongs to the pharmaceutics technical field, also belongs to the macromolecular material field that learns a skill.
Diclofenac sodium (having another name called diclofenac, Sodium Diclofenac) is widely used clinically potent NSAID (non-steroidal anti-inflammatory drug), has unique antiinflammatory, eases pain, separates thermal effect.The pain and the heating that cause for rheumatoid arthritis, rheumatism osteoarthritis, ankylosing arthritis, neuritis, red class trace skin ulcer, cancer postoperative pain and various inflammation all have definite curative effect.
The pharmacological action of diclofenac sodium and other NSAID (non-steroidal anti-inflammatory drug) is the same, all is to stop by arachidonic acid by epoxidase in the inhibition body to be converted into prostaglandin, and prostaglandin is one of important inflammatory mediator that destroys in the joint.The inflammation-inhibiting reaction is the key of rheumatoid arthritis treatment success effectively.
When diclofenac sodium during with drug administration by injection, rectally, oral administration; because whole body absorbs; the gastrointestinal mucosa prostaglandin is synthetic to be suppressed, and takes medicine for a long time stomach bicarbonate radical and mucous secretion are reduced, and gastric mucosal barrier destroys; cell loses protective effect; can cause ulcer and hemorrhage, 31% patient has Gastric Diseases by Spraying after taking medicine 1 year, takes its pathological changes rate of multiple person up to 51%; have also with central nervous system's untoward reaction, as headache, dizziness etc.
The rise of the 1980's preparation capable of permeating skin has brought new opportunity for the developing of non-steroidal anti-inflammatory pharmaceutically dosage form, arise at the historic moment as liniment, gel etc., but this class preparation exists and needs repeatedly embrocate in one, and easily problem such as wipe for medicated clothing.
The diclofenac sodium transdermal absorbable preparation of United States Patent (USP) (USP4738848) invention adds a certain amount of organic acid in medicated layer makes it change free diclofenac into, with the extremely strong barrier action of solution skin to ionic drug, but this preparation can only be with the lipotropy macromolecular material as pressure sensitive adhesive matrix; Not only environment is polluted on the technology; Physical property is poor, causes the peeling force height and infringement skin; Then destroy the shoe lid effect of plaster as open pore, influence drug transdermal and absorb.
Chinese patent (number of patent application is 95102534.1), it be the inventor we be substrate with the hydrophilic high molecular material, successfully be developed into NSAID (non-steroidal anti-inflammatory drug) molecule-type medicine indomethacin percutaneous controlled-release plaster, and obtained the New Drug Certificate that Ministry of Public Health is issued on the 2nd, certificate number: (96) medicine authorized No. X-206 number in December in 1996.It is still the potent NSAID (non-steroidal anti-inflammatory drug) of a kind of transdermal molecule-type, is the transdermal absorption formulation that adopts hydrophilic matrix to produce.
The objective of the invention is: it is effective ingredient with the ionic drug diclofenac sodium that inventor of the present invention intends research and development, is the novel diclofenac sodium skin-penetrating delayed plaster of substrate with hydrophilic acrylic copolymer pressure sensitive adhesive.It should be able to form compound transdermal enhancer with ethanol, propylene glycol, glycerol, PEG300, PEG400, azone, Herba Menthae, carbamide, Camphora, Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods material, make novel diclofenac sodium skin-penetrating delayed plaster, when expecting that this plaster is affixed on affected part, diclofenac sodium can absorb by percutaneous, the topica concentration of pasting the medicine position will be far above blood drug level, and energy long action time, nonirritant, nothing are peeled off reaction, the novel percutaneous controlled-release plaster that also should not have GI irritation and the central nervous system is had no adverse reaction.
Be the technical measures that realize that purpose of the present invention is taked:
The present invention is novel transdermal therapeutic system, i.e. a diclofenac sodium skin-penetrating delayed plaster.
The main component that can produce anti-inflammatory pain-stopping effect among the present invention is a diclofenac sodium.Diclofenac sodium is the potent NSAID (non-steroidal anti-inflammatory drug) of life-time service clinically.In diclofenac sodium skin-penetrating delayed plaster of the present invention, the consumption of diclofenac sodium is 0.08～15.0%.
Among the present invention, this percutaneous controlled-release plaster adopts and comprises that the hydrophilic macromolecular material of acrylate polymer pressure sensitive adhesive is a substrate.Acrylate pressure-sensitive adhesive just is used to prepare medical adhesive tape abroad from nineteen sixty generation.Itself is minimum to skin irritation, need not add viscosifier, antioxidant, seldom causes allergic reaction, and the acrylate polymer pressure sensitive adhesive of possess hydrophilic property also has the characteristics of poisture-penetrability.The acrylate polymer pressure sensitive adhesive that the present invention is selected, its standard have recorded the pharmaceutic adjuvant handbook into the U.S., have very high safety.The consumption of acrylate polymer pressure sensitive adhesive is comparatively suitable with 40.0～98.0% among the present invention.
Among the present invention, though adopt diclofenac sodium for producing the principal agent composition of drug effect, and diclofenac sodium is when being ionic drug, the barrier action of skin when being difficult to overcome medicine and seeing through skin.So in percutaneous controlled-release plaster of the present invention, adopt compound transdermal enhancer, as low mass molecule alcohol classes such as propylene glycol, glycerol, PEG300, PEG400, and for example carbamide, Herba Menthae, azone, Camphora, Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods, the transdermal enhancer that the present invention uses is for selecting two or more compound transdermal enhancer arbitrarily for use from these transdermal enhancers, its consumption is 1.0～20.0%.
Among the present invention, the compound transdermal enhancer and the hydrophilic acrylic resin pressure sensitive adhesive mix homogeneously that the principal agent composition diclofenac sodium of diclofenac sodium skin-penetrating delayed plaster are comprised low mass molecule alcohol class, carbamide, azone, Camphora, Herba Menthae, eucalyptus oil, make solid dispersion on base paper with the transitivity coating then, through 70 ℃～150 ℃ dryings, then with comprising that the backing material of mounting of PVC thin film or non-woven fabrics carries out compound, be die-cut into a certain size and specification, promptly obtain the diclofenac sodium skin-penetrating delayed plaster product.
Compared with the prior art, the technique effect that reached of the present invention:
The diclofenac sodium skin-penetrating delayed plaster of the present invention's preparation has the effect of good anti-inflammatory and antalgic, and has no adverse reaction, its Transdermal absorption test, and pharmacodynamics and toxicology test result are as follows.
1. Transdermal absorption test
Transdermal absorption in vitro tests development is rapid, and it is accurate and reliable measuring its diffusion at external skin by the people, and former low dose of isotope-labeled animal model is derived correlative factor with low dose of intravenous injection, and its experimental error is huge.The in vitro study that animal skin is compared with human body skin is increasing, Franz has made significant contribution in this respect, he has also designed and has limited the quantity of diffusion cell or claim the Franz diffusion cell, has further estimated limited dosimetry and has made the inside and outside data keep closer dependency.The present invention adopts the static diffusion chamber Keshary-chien diffusion of the single compartment of improved Franz Xiao Chi, overcome some defective that Franz diffusion Xiao Chi is used for the Transdermal absorption test, adopt with the Periostracum Serpentis of application on human skin horny layer fairly similar and make barrier [Harada, etal.J.Pharm, Pharmacol, 1993 (45), 414-418], its experimental result such as table 1.
Table 1 diclofenac sodium transdermal diffusion test
Test shows that principal agent transit dose in the diclofenac sodium skin-penetrating delayed plaster is much higher than the blood peak concentration of drug (about 1 μ g/ml) of oral this medicine, and long action time, has controlled-release effect, points out this diclofenac sodium skin-penetrating delayed plaster to have good drug effect.
2. results of pharmacodynamic test
2.1 the diclofenac sodium skin-penetrating delayed plaster on Carrageenan is brought out the therapeutical effect of rat toes edema
Press Xu Shuyun etc. compile " pharmacological testing methodology " (the nineteen eighty-two version, P525) Ji Zai method is tested: get 20 of male SD rats, be divided into two groups at random, 10 every group, before the experiment with the volumetric values below every the right back ankle of rat joint of volumetric method mensuration.The 1st group of right back toe of every Mus position sticks blank plaster, as negative control; The 2nd group sticks diclofenac sodium skin-penetrating delayed plaster, administration was peeled off plaster after 4 hours, carrageenin at every the right back toe of Mus middle part subcutaneous injection 0.05ml1.0%, behind the Yu Zhiyan 1,3, tested each following volumetric values in rat ankle joint in 5 hours, calculate swelling degree and suppression ratio according to formula (1) and formula (2).Its experiment the results are shown in table 2.
V in the formula (1)
nAnd V
tRepresentative causes the swelling value of scorching front and back respectively.
E in the formula (2)
tAnd E
cRepresent the average swelling degree of administration group and blank group respectively.
It is big that table 2 diclofenac sodium plaster on Carrageenan is brought out
The therapeutical effect of Mus toes edema
*P＜0.01
The result shows that the diclofenac sodium plaster can significantly suppress the toes inflammation that carrageenin brings out.
2.2. the therapeutical effect of the rat arthritis that diclofenac sodium skin-penetrating delayed plaster brings out Freund's complete adjuvant
Pressing Xu Shuyun etc. compiles " pharmacological experimental methodology " (the nineteen eighty-two version, P534) Ji Zai method test: getting SD is rat was all measured the following normal foot pawl in left and right hind leg ankle joint with volumetric method before medication displacement.After this, after injection not causes scorching 300min for Freund's complete adjuvant 0.1ml in the right back toes of every Mus, stick and contain medicine plaster, dosage is 30mg/kgwt, immobilization with adhesive tape, every group causes scorching back 1,2,3 days, in kind change dressings once for every group with dosage, after causing scorching back 18 hours and 3 days, measure right back sufficient displacement with volumetric method, observe of the influence of diclofenac sodium plaster to the constitutional inflammation.Causing to continue to use the same method in one week in scorching back and identical dosage sticks for reagent thing 7 days every group of rat, promptly cause scorching back measured in the 14th day left and right after the swelling value of toes.Observe of the influence of diclofenac sodium plaster to secondary inflammation, after causing scorching 19 days, change dressings once with said method and dosage, continuous use 7 days is observed the therapeutical effect of diclofenac sodium plaster to secondary inflammation, calculates swelling degree and suppression ratio by above-mentioned formula (1) and formula (2).Its experiment the results are shown in table 3, table 4, table 5.
Table 3 diclofenac sodium plaster is to the influence of constitutional pathological changes
| Group | After causing scorching 18 hours | After causing scorching 3 days | ||
| Swelling degree (the ml of x ± s) | Suppression ratio (%) | Swelling degree (the ml of x ± s) | Inhibition degree (%) | |
| Blank group (n=10) | ??0.29±0.03 | ??0.72±0.03 | ||
| Plaster group (n=10) | ??0.12±0.02 * | ????58.62 | 0.17 the scholar 0.02 * | ????76.39 |
*P＜0.01
Table 4 diclofenac sodium plaster is to the influence (causing a disease back 14 days) of Secondary cases pathological changes
| Group | Left back foot | Right back foot | ||
| Swelling degree (the ml of x ± s) | Suppression ratio (%) | Swelling degree (the ml of x ± s) | Inhibition degree (%) | |
| Blank group (n=10) | ??0.36±0.03 | ????0.74±0.06 | ||
| Plaster group (n=10) | ??0.11±0.04 * | ????69.44 | ????0.14±0.0 2* | ????81.08 |
*P＜0.01
Table 5 diclofenac sodium plaster is to the effect (after causing a disease 26 days) of Secondary cases pathological changes
| Group | Left back foot | Right back foot | ||
| Swelling degree (the ml of x ± s) | Suppression ratio (%) | Swelling degree (the ml of x ± s) | Inhibition degree (%) | |
| Blank group (n=10) | ??0.29±0.03 | ??0.63±0.05 | ||
| Plaster group (n=10) | ??0.08±0.03 * | ?72.41 | ??0.08±0.04 * | ??87.30 |
* compare with the blank group in P＜0.01
Above-mentioned test shows: the prepared diclofenac sodium skin-penetrating delayed plaster of the present invention can obviously suppress the rat arthritis that Freund's complete adjuvant brings out.
3. toxicological test
The diclofenac sodium raw materials is irritated the LD of stomach (oral) administration
50Be 117mg/kg, with the LD of bibliographical information
50Be the 105mg/kg unanimity.And the diclofenac sodium plaster, press the disposable external application of maximal dose (105mg/kg) after 24 hours, do not see that any toxic and side effects takes place, this dosage clinical with dosage 84 times of behaving, visible diclofenac sodium skin-penetrating delayed plaster external curing rheumatic arthritis of the present invention be safety, reliable, have no side effect.
Below in conjunction with embodiment the present invention is described in further detail.
Embodiment 1:
Prescription: diclofenac sodium 1.0%
Ethanol 2.0%
Azone 1.0%
Acrylate copolymer 96.0%
Technology: with said medicine and adjuvant mix homogeneously, make solid dispersion on base paper with the transitivity coating, through 70～90 ℃ of dryings, the composite PVC thin film is die-cut into 7.3 * 7.3cm then
2Size promptly gets diclofenac sodium skin-penetrating delayed plaster.
Embodiment 2:
Prescription: diclofenac sodium 1.0%
Ethanol 3.0%
Propylene glycol 2.0%
Azone 3.0%
Acrylate copolymer 91.0%
Technology is with embodiment 1.
Embodiment 3:
Prescription: diclofenac sodium 2.0%
Ethanol 5.0%
Herba Menthae 3.0%
Azone 1.0%
Acrylate copolymer 89.0%
Technology is with embodiment 1.
Claims (5)
1. the diclofenac sodium skin-penetrating delayed plaster of novel medicament percutaneous controlled-release treatment usefulness, it is characterized in that: by principal agent diclofenac sodium, hydrophilic pressure sensitive gel matrix, compound transdermal enhancer, behind abundant mix homogeneously, coat on the base paper, reuse comprise PVC or non-woven fabrics to mount backing material transitivity compound, produce diclofenac sodium skin-penetrating delayed plaster.
2. by the described diclofenac sodium skin-penetrating delayed plaster of claim 1, it is characterized in that: the consumption of diclofenac sodium is 〉=0.08% to 15.0%.
3. by the described diclofenac sodium skin-penetrating delayed plaster of claim 1, it is characterized in that: selected host material is hydrophilic acrylate polymer pressure sensitive adhesive, and its consumption is 〉=45.0% to 98.0%.
4. by the described diclofenac sodium skin-penetrating delayed plaster of claim 1, it is characterized in that: the selected compound transdermal enhancer that comprises ethanol, propylene glycol, glycerol, PEG300, PEG400 low mass molecule alcohol class, azone, carbamide, Herba Menthae, Camphora, eucalyptus oil, two or more that adopts these transdermal enhancers is compound, and consumption is 〉=1.0% to 20.0%.
5. by the described diclofenac sodium skin-penetrating delayed plaster of claim 1, it is characterized in that: preparation technology is with principal agent composition diclofenac sodium, acrylate copolymer pressure sensitive adhesive and compound transdermal enhancer fully mix, solid dispersion is made on base paper with the transitivity coating in the back, through 70～150 ℃ of dryings, then with comprise PVC or non-woven fabrics to mount the backing material compound, be die-cut into a certain size, specification, promptly produce diclofenac sodium skin-penetrating delayed plaster.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97109086 CN1174031A (en) | 1997-04-23 | 1997-04-23 | Diclofenac sodium skin-penetrating delayed plaster |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 97109086 CN1174031A (en) | 1997-04-23 | 1997-04-23 | Diclofenac sodium skin-penetrating delayed plaster |
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| CN1174031A true CN1174031A (en) | 1998-02-25 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319229A (en) * | 2011-07-27 | 2012-01-18 | 蚌埠丰原涂山制药有限公司 | Preparation method of diclofenac sodium transdermal patch |
| CN105708823A (en) * | 2016-04-08 | 2016-06-29 | 中国药科大学 | Long-acting diclofenac transdermal patch and preparation technology thereof |
| EP3490541A2 (en) * | 2016-07-27 | 2019-06-05 | Corium International, Inc. | Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs byin situ |
| US11173132B2 (en) | 2017-12-20 | 2021-11-16 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
| US11541018B2 (en) | 2016-06-23 | 2023-01-03 | Corium, Llc | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
| US12161767B2 (en) | 2015-12-30 | 2024-12-10 | Corium, Llc | Systems and methods for long term transdermal administration |
-
1997
- 1997-04-23 CN CN 97109086 patent/CN1174031A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102319229A (en) * | 2011-07-27 | 2012-01-18 | 蚌埠丰原涂山制药有限公司 | Preparation method of diclofenac sodium transdermal patch |
| US12161767B2 (en) | 2015-12-30 | 2024-12-10 | Corium, Llc | Systems and methods for long term transdermal administration |
| US12168075B2 (en) | 2015-12-30 | 2024-12-17 | Corium, Llc | Systems comprising a composite backing and methods for long term transdermal administration |
| CN105708823A (en) * | 2016-04-08 | 2016-06-29 | 中国药科大学 | Long-acting diclofenac transdermal patch and preparation technology thereof |
| US11541018B2 (en) | 2016-06-23 | 2023-01-03 | Corium, Llc | Adhesive matrix with hydrophilic and hydrophobic domains and a therapeutic agent |
| EP3490541A2 (en) * | 2016-07-27 | 2019-06-05 | Corium International, Inc. | Transdermal formulation and delivery method of low solubility or unstable unionized neutral drugs byin situ |
| US11103463B2 (en) | 2016-07-27 | 2021-08-31 | Corium, Inc. | Methods for treating alzheimer's disease with donepezil transdermal system |
| US11173132B2 (en) | 2017-12-20 | 2021-11-16 | Corium, Inc. | Transdermal adhesive composition comprising a volatile liquid therapeutic agent having low melting point |
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